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Sant'Ambrogio di Torino, Italy

Catalano M.G.,University of Turin | Fortunati N.,Oncological Endocrinology | Boccuzzi G.,University of Turin
Frontiers in Endocrinology | Year: 2012

At present no successful treatment is available for advanced thyroid cancer, which comprises poorly differentiated, anaplastic, and metastatic or recurrent differentiated thyroid cancer not responding to radioiodine. In the last few years, biologically targeted therapies for advanced thyroid carcinomas have been proposed on the basis of the recognition of key oncogenic mutations. Although the results of several phase II trials look promising, none of the patients treated had a complete response, and only a minority of them had a partial response, suggesting that the treatment is, at best, effective in stabilizing patients with progressive disease. "Epigenetic" refers to the study of heritable changes in gene expression that occur without any alteration in the primary DNA sequence. The epigenetic processes establish and maintain the global and local chromatin states that determine gene expression. Epigenetic abnormalities are present in almost all cancers and, together with genetic changes, drive tumor progression. Various genes involved in the control of cell proliferation and invasion (p16INK4A, RASSF1A, PTEN, Rap1GAP, TIMP3, DAPK, RARβ2, E-cadherin, and CITED1) as well as genes specific of thyroid differentiation (Na+/I- sym-port, TSH receptor, pendrin, SL5A8, and TTF-1) present aberrant methylation in thyroid cancer. This review deals with the most frequent epigenetic alterations in thyroid cancer and focuses on epigenetic therapy, whose goal is to target the chromatin in rapidly dividing tumor cells and potentially restore normal cell functions. Experimental data and clinical trials, especially using deacetylase inhibitors and demethylating agents, are discussed. © 2012. Catalano, Fortunati and Boccuzzi. Source

Catalano M.G.,University of Turin | Pugliese M.,University of Turin | Gargantini E.,University of Turin | Grange C.,University of Turin | And 9 more authors.
International Journal of Cancer | Year: 2012

Anaplastic thyroid carcinoma (ATC) has a rapidly fatal clinical course, being resistant to multimodal treatments. Microtubules, α/β tubulin heterodimers, are crucial in cell signaling, division and mitosis and are among the most successful targets for anticancer therapy. Panobinostat (LBH589) is a potent deacetylase inhibitor acting both on histones and nonhistonic proteins, including α-tubulin. In vitro LBH589, evaluated in three ATC cell lines (BHT-101, CAL-62 and 8305C), resulted in impairment of cell viability, inhibition of colony formation, cell cycle arrest and apoptosis induction. Mechanistically, we showed that LBH589 not only affected the expression of p21 and cyclin D1, but markedly determined microtubule stabilization as evidenced by tubulin acetylation and increased tubulin polymerization. In a SCID xenograft model implanted with CAL-62 cells, the cytotoxic properties of LBH589 were confirmed. The drug at the dose of 20 mg/kg significantly impaired tumor growth (final tumor volume 2.5-fold smaller than in untreated animals); at this dose, no relevant side effects were observed. In tumors of treated animals, a significant reduction of Ki67, which was negatively correlated with tubulin acetylation, was observed. Moreover, acetyl-tubulin levels negatively correlated with tumor volume at sacrifice, reinforcing the opinion that tubulin acetylation has a role in the inhibition of tumor growth. In conclusion, LBH589, acting on both histones and nonhistonic proteins in anaplastic thyroid cancer, appears to be a promising therapeutic agent for the treatment of this kind of cancer which is known not to respond to conventional therapy. Copyright © 2011 UICC. Source

Rinella L.,University of Turin | Marano F.,University of Turin | Berta L.,Med and Sport 2000 Srl | Bosco O.,University of Turin | And 4 more authors.
Wound Repair and Regeneration | Year: 2016

Mesenchymal stem cells are precursors of myofibroblasts, cells deeply involved in promoting tissue repair and regeneration. However, since myofibroblast persistence is associated with the development of tissue fibrosis, the use of tools that can modulate stem cell differentiation toward myofibroblasts is central. Extracorporeal shock waves are transient short-term acoustic pulses first employed to treat urinary stones. They are a leading choice in the treatment of several orthopedic diseases and, notably, they have been reported as an effective treatment for patients with fibrotic sequels from burn scars. Based on these considerations, the aim of this study is to define the role of shock waves in modulating the differentiation of human adipose-derived stem cells toward myofibroblasts. Shock waves inhibit the development of a myofibroblast phenotype; they down-regulate the expression of the myofibroblast marker alpha smooth muscle actin and the extracellular matrix protein type I collagen. Functionally, stem cells acquire a more fibroblast-like profile characterized by a low contractility and a high migratory ability. Shock wave treatment reduces the expression of integrin alpha 11, a major collagen receptor in fibroblastic cells, involved in myofibroblast differentiation. Mechanistically, the resistance of integrin alpha 11-overexpressing cells to shock waves in terms of alpha smooth muscle actin expression and cell migration and contraction suggests also a role of this integrin in the translation of shock wave signal into stem cell responses. In conclusion, this in vitro study shows that stem cell differentiation toward myofibroblasts can be controlled by shock waves and, consequently, sustains their use as a therapeutic approach in reducing the risk of skin and tissue fibrosis. © 2016 by the Wound Healing Society. Source

Catalano M.G.,University of Turin | Poli R.,University of Turin | Pugliese M.,University of Turin | Fortunati N.,Oncological Endocrinology | Boccuzzi G.,University of Turin
Molecular Aspects of Medicine | Year: 2010

Advanced thyroid cancer refers to thyroid tumors which are resistant to conventional therapies and do not respond to radioiodine and comprises metastatic or recurrent differentiated cancers, poorly differentiated and anaplastic tumors. Progress in the knowledge of genetic/epigenetic alterations in thyroid cancer cells is rapidly offering several opportunities to develop new drugs directed to specific targets.Drugs currently proposed for molecular therapy include: (a) monoclonal antibodies; (b) kinase inhibitors; (c) anti-angiogenetic drugs; (d) proteasome inhibitors; (e) retinoic acid and PPAR-γ ligands; (f) radionuclide therapy; (g) epigenetic drugs (deacetylase inhibitors and demethylating agents). The results of several phase II trials using molecular drugs look promising. None of the treated patients, however, had a complete response, and only a minority of them had a partial response.The review will focus especially on epigenetic therapy, whose goal is to target the chromatin in rapidly dividing tumor cells and potentially restore normal cell functions. Deacetylases inhibitors modulate both epigenetic and multiple non-epigenetic mechanisms; they are, thus, viewed as a promising class of anticancer drugs. Experimental data show that deacetylase inhibitors are effective against advanced thyroid cancer.However, since multiple pathways need to be inhibited in order to substantially affect thyroid cancer growth, it is likely that a significant increase in the response rate to treatment of advanced thyroid cancer will be achieved through combinatorial drug therapies. Actually, many pre-clinical and clinical studies evaluate the combination of either two epigenetic drugs or a non-epigenetic chemotherapeutic and an epigenetic drug, in the effort to increase response rates. © 2010 Elsevier Ltd. Source

Finocchiaro C.,San Giovanni Battista Hospital | Segre O.,San Giovanni Battista Hospital | Fadda M.,San Giovanni Battista Hospital | Monge T.,San Giovanni Battista Hospital | And 12 more authors.
British Journal of Nutrition | Year: 2012

PUFA from fish oil appear to have anti-inflammatory and anti-oxidative effects and improve nutritional status in cancer patients. With this as background, the aim of the present study was to investigate the effect of EPA plus DHA on inflammatory condition, and oxidative and nutritional status in patients with lung cancer. In our multicentre, randomised, double-blind trial, thirty-three patients with a diagnosis of advanced inoperable non-small-cell lung cancer and undergoing chemotherapy were divided into two groups, receiving four capsules/d containing 510 mg of EPA and 340 mg of DHA, or 850 mg of placebo, for 66 d. At the start of chemotherapy (T 0), after 8 d (T 1), 22 d (T 2) and 66 d (T 3), biochemical (inflammatory and oxidative status parameters) and anthropometric parameters were measured in both groups. A significant increase of body weight in the n-3 group at T 3 v. T0 was observed. Concerning inflammation, C-reactive protein and IL-6 levels differed significantly between the n-3 and placebo groups at T 3, and progressively decreased during chemotherapy in the n-3 group, evidencing n-3 PUFA anti-inflammatory action. Concerning oxidative status, plasma reactive oxygen species levels increased in the placebo group v. the n-3 group at the later treatment times. Hydroxynonenal levels increased in the placebo group during the study, while they stabilised in the n-3 group. Our data confirm that the continual assumption of EPA plus DHA determined an anti-inflammatory and anti-oxidative action which could be considered a preliminary goal in anti-cachectic therapy. © 2011 The Authors. Source

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